Traditional measures of bioavailability have focused on the ability to deliver a pharmaceutical agent to the blood stream. In fact, "bioavailability" is often defined as the concentration of a drug in the bloodstream after administration. This is misleading, however, because the blood, in most cases, is not the target tissue for drug action. The true site for drug action is often tissues outside of the vascular system, such as muscles, nerves, organs, etc. The actual concentration of a drug in the interstitial fluid surrounding target cells, and therefore in target cells, can be much lower than what is seen in the blood, because the vascular endothelium and tissue integrity forms a barrier to drug delivery.
Although some pharmaceutical materials can readily diffuse through all endothelial barriers and interstitial tissues, they often have a large volume of distribution and low target specificity, so that high doses are needed to achieve a therapeutic response. Many macromolecular pharmaceutical agents, including genetic materials, polypeptides, anti-sense polynucleotides, liposomes, and polymers used as drug carriers, are not effective in vivo due to their inability to penetrate the endothelial barrier and interstitial tissues and reach their target sites.
For example, possible therapeutic agents for diseases in the brain are often rendered useless because they cannot penetrate the blood brain barrier. Chemotherapy for the treatment of cancer is also dramatically altered by vascular permeability and tissue integrity. Liposomes loaded with doxorubicin are 20 times more effective than the free drug in Kaposi's Sarcoma because the liposomes can accumulate in the tumor due to "leaky" endothelium in the tumor vessels. Finally, key cytokines in the inflammatory process, such as tumor necrosis factor and interleukins, are involved in changing the permeability of the vasculature and delivery of pharmaceutical agents. These agents play a key role in the pathophysiology of ischemic and inflammatory diseases.
There is a need in the field for methods of preferential delivery of pharmaceutical agents to specific target tissues within the body. The present invention addresses this problem.
Relevant Literature
Bednarski et al. (1997) Radiology 204:263-268 discloses the targeted delivery of liposomes encapsulating gadopentetate dimeglumine into muscle tissue. Abstracts were published by Bednarski et al. (1996) disclosing the transfection of cultured cells with liposome encapsulated DNA using ultrasound.
Devices have been developed that focus ultrasonic sound waves at a focal point deep within tissues of a subject. At the focal point, energy is dissipated and local heating results. U.S. Pat. No. 5,247,935, "Magnetic resonance guided focused ultrasound surgery" discloses performance of surgery with a focused ultrasound transducer that selectively destroys tissue in a targeted region. A similar system for focused ultrasound is utilized in the methods of U.S. Pat. No. 5,490,840, which discloses methods of using localized heat to release drugs from carrier molecules at a target site.
U.S. Pat. No. 5,614,502 and U.S. Pat. No. 5,658,892, Flotte et al., disclose a method of increasing delivery of a compound across a cell membrane. The cell is exposed to a high pressure impulse that alters the membrane permeability in the presence of the target compound. A number of patents have issued relating to the use of ultrasound to deliver drugs to the skin, including: U.S. Pat. No. 5,445,611; U.S. Pat. No. 4,767,402; U.S. Pat. No. 5,267,985; U.S. Pat. No. 4,948,587; U.S. Pat. No. 5,115,805; U.S. Pat. No. 5,656,016; and U.S. Pat. No. 5,421,816.
Bao et al. (1997) Ultrasound Med Biol 23:953-959 report the transfection of a reporter plasmid into cultured cells by sonoporation. Tata et al. (1997) Biochem Biophys Res Commun 234(1):64-67 utilized low intensity ultrasound signals to mediate differential gene transfer and expression of a reporter plasmid in two human prostate cancer cell lines. Kim et al. (1996) Hum Gene Ther 7:1339-1346 transfected with plasmid DNA in vitro using ultrasound transmitted through the walls of cell culture flasks or plates.